Fri Oct 21 2022

78 articles - From Friday Oct 14 2022 to Friday Oct 21 2022

parm_toc.knit

Guidelines

Guidelines, position statements, white papers, technical reviews, consensus statements, etc…


Meta-analysis

meta-analyses and systematic reviews

Blood Adv

Toxicity and Efficacy of CAR T-cell Therapy in PCNSL and SCNSL: A Meta-Analysis of 128 Patients.

In a large meta-analysis of CNS lymphomas, toxicity of anti-CD19 CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.

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Leukemia

Association of hematologic response and assay sensitivity on the prognostic impact of measurable residual disease in acute myeloid leukemia: a systematic review and meta-analysis.

The beneficial impact of MRD negativity was observed across MRD assays and timing of MRD assessment. In patients with AML in morphological remission, achievement of MRD negativity is associated with superior DFS and OS, irrespective of hematologic response or the MRD threshold used.

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Original articles

RCT, clinical trials, retrospective studies, etc…

Am J Hematol

Allogeneic hematopoietic cell transplantation in patients with CML chronic phase in the era of third generation tyrosine kinase inhibitors: a retrospective study by the Chronic Malignancies Working Party of the EBMT.

No difference in OS, PFS, RI or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI (p=ns). Significant factors influencing OS and PFS were >CP1 vs CP1 and Karnofsky performance (KPS) score >80 vs =80, highlighting CP1 patients undergoing allo-HCT have improved survival compared to >CP1 and the importance of careful allo-HCT candidate selection.

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Follicular lymphoma: 2023 update on diagnosis and management.

Lenalidomide was non-inferior to chemoimmunotherapy in a randomized front-line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, stem cell transplantation (SCT), and chimeric antigen receptor T cells (CAR-T) are also considered for recurrent disease.

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Health-related quality of life in reduced intensity hematopoietic cell transplantation based on donor availability in patients aged 50-75 with advanced myelodysplastic syndrome: BMT CTN 1102.

For older adults with MDS, the survival advantage associated with Donor availability and alloHCT did not come at the cost of worse QOL. These results should reassure older patients and clinicians who prefer a curative approach to treating MDS.

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Impact of Academic Medical Center Access on Outcomes in Multiple Myeloma.

On this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.

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Impact of adherence to hydroxyurea on health outcomes among patients with sickle cell disease.

After adjustment for demographic and clinical characteristics, compared to being non-adherent, adhering to hydroxyurea was significantly associated with: a lower risk (Odds Ratio [OR]=0.480, p=0.0007) and hazard rate (Hazard Ratio [HR]=0.748, p=0.0005) of a VOC event, fewer VOC events (Incidence Rate Ratio [IRR]=0.767, p=0.0009), fewer VOC-related hospital days (IRR=0.593, p=0.0003), fewer all-cause and SCD-related hospitalizations (IRR=0.712, p=0.0008; IRR=0.707, p=0.0008, respectively) and emergency department visits (IRR=0.768, p=0.0037; IRR=0.746, p=0.0041, respectively), and lower SCD-related total healthcare expenditures (IRR=0.796, p=0.0266). Efforts to increase adherence to hydroxyurea could improve clinical and economic outcomes among individuals with SCD.

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Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia.

Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

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Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multi-center observational study.

Our findings indicate that two doses of SARS-CoV-2 vaccine is safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

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Ann Oncol

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high risk, early breast cancer.

With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

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Blood

Aberrant function of pathogenic STAT3 mutant proteins is linked to altered stability of monomers and homodimers.

Of note, a small-molecule inhibitor of STAT3 that targets the pY-peptide binding pocket within the STAT3 SH2D potently inhibited cell proliferation driven by STAT3 SH2D GOF mutants. These findings indicate that stability of STAT3 protein monomer and homodimer is critical for the pathogenesis of diseases caused by SH2D LOF and GOF mutations and suggest that agents that modulate STAT3 monomer and/or homodimer protein stability may have therapeutic value in diseases caused by these mutations.

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An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm AML patients.

Accounting for health impairments negate survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is due mostly to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT.

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NGS better discriminates true MRD positivity for the risk stratification of childhood ALL treated on MRD-based protocol.

Risk group stratification based on the MRD results by qPCR and NGS at EOI was concordant in 76% of the patients, 19% of the patients would be assigned to a lower-risk group by NGS, largely due to the elimination of false-positive qPCR results, and 5% of patients would be assigned to a higher risk group by NGS. NGS MRD is highly concordant with qPCR while providing more specific results and can be an alternative in the frontline MRD evaluation in forthcoming MRD-based protocols.

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Venetoclax and idasanutlin in relapsed/refractory AML: a non-randomized, open-label phase 1b trial.

IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were pre-existing. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations.

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Blood Adv

A mouse model characterizes the roles of ZIP8 in systemic iron recycling and lung inflammation and infection.

LPS-induced inflammation induced ZIP8 expression in the lung, but ZIP8 deletion had no detrimental effect on the severity of LPS-induced acute lung injury or on the outcomes of Klebsiella pneumoniae lung infection. Thus, ZIP8 plays a role in systemic iron homeostasis but does not modulate the severity of inflammatory lung injury or the host defense against a common bacterial cause of pneumonia.

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Analysis of Disparities in Time to Allogeneic Transplantation in Adults with Acute Myelogenous Leukemia.

HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and utilize al alternative donor sources are critical to ensure timely transplantation for AML patients.

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Distinct clonal identities of B-ALLs arising after Lenolidomide therapy for multiple myeloma.

The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

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Evaluation of four prognostic indices in follicular lymphoma treated in first line with immunochemotherapy.

When analyzed only R-B patients, m7-FLIPI had higher discrimination for PFS and OS. Thus, FLIPI remains as the clinical risk score with higher discrimination in advanced FL patients treated with immunochemotherapy, but the performance of m7-FLIPI should be further investigated in patients treated with R-B.

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Integrated flow cytometry and sequencing to reconstruct evolutionary patterns from dysplasia to acute myeloid leukemia.

Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in approximately 80% of newly diagnosed AML patients, using techniques other than single-cell multiomics.

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Mechano-covalent protection of coagulation factor VIII by von Willebrand factor.

Exposure of VWF to pathological fluid shear forces ex vivo and in vivo causes partial cleavage of al 13 disulfide bonds, further supporting their malleable nature. These findings demonstrate that FVIII binding to VWF involves dynamic changes in the covalent states of several VWF disulfides that are required for productive interaction in physiological shear forces.

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Novel insights into mouse models of ectopic proplatelet release.

WASp-deficient MKs showed the strongest reduction in the adhesion assay on collagen and altered F-actin organization with reduced podosome formation. Our results indicate that ADAP, PFN1, WASp and ARP2/3 are part of the same pathway, which regulates polarization processes in megakaryocytes and directional proplatelet formation into bone marrow sinusoids.

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Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease.

VOEs requiring medical care are significantly reduced after allogeneic HSCT for patients with SCD. These data should inform the results of newer autologous HSCT gene therapy approaches.

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Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation.

Further studies are needed to determine the contexts where targeting FXI and FXII, either alone or in combination, would be most beneficial in ECMO. Further studies are also needed to determine the potential mechanisms coupling FXII to end organ damage in ECMO.

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The consortium on newborn screening in Africa for sickle cell disease: study rationale and methodology.

Effectiveness of these early interventions, along with culturally appropriate family education and counseling, will be evaluated by comparing U5 mortality in the enrolled cohort to estimated pre-program data. Here we describe the methodology planned for this trial.

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The Gut Microbiota in Patients with Polycythemia Vera is Distinct from that of Healthy Controls and Varies by Treatment.

The observations are highly interesting considering the potential pathogenetic importance of an altered gut microbiota for development of other diseases, including chronic inflammatory diseases. Our observations call for further gut microbiota studies to decipher potential causal associations between treatment and the gut microbiota in PV and related neoplasms.

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Transformation of FL into DLBCL with a PMBL gene expression signature.

Despite having some features that are less common in DLBCL (MAL and CD23 expression, JAK-STAT activation), these tFL-PMBLsig-pos cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with gene expression and some genetic features reminiscent of PMBL, with potential treatment implications that include the use of novel targeted therapies.

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Haematologica

BCMA loss in the epoch of novel immunotherapy for multiple myeloma: from biology to clinical practice.

Therefore, strategies to overcome this kind of drug resistance are needed for these patients. In this review, we will discuss the loss of BCMA in the new epoch of immunotherapy for MM.

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Cytomegalovirus reactivation after CD19 CAR T cell therapy is clinically significant.

Not available.

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Enhancing regulatory T cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia.

These results indicated that 18ß-GA has the potential to restore immune balance in ITP via inhibition of HMGB1 signaling. In short, this study reveals the role of HMGB1 in ITP, which may serve as a potential target for thrombocytopenia therapy.

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Pathology review identifies frequent misdiagnoses in recurrent classic Hodgkin lymphoma in a nation-wide cohort: Implications for clinical and epidemiological studies Authors.

Based on these data, risk to develop NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; CI 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for individual patient care, interpretation of trials and epidemiological assessments.

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Prognostic value of positron emission tomography/computed tomography in transplanteligible newly diagnosed multiple myeloma patients from CASSIOPEIA: the CASSIOPET study.

Not available.

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The real risk of secondary non-Hodgkin lymphoma following Classical Hodgkin lymphoma.

Not available.

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Three-year results from phase 1 of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia.

Pediatric/adolescent patients with R/R B-ALL achieved high MRD-negative remission rates with manageable safety profile after a single dose of KTE-X19. Phase 2 is ongoing at the 1×106 CAR T cells/kg (40 mL) dose.

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Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study.

Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved complete response in later LoT, and duration of response and survival diminished with each subsequent line.

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Lancet Haematol

UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial.

This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. Funding Servier.

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Leukemia

DDX41 coordinates RNA splicing and transcriptional elongation to prevent DNA replication stress in hematopoietic cells.

Although the degree of DNA replication stress acquired in S phase is small, cells undergo mitosis with under-replicated DNA being remained, resulting in micronuclei formation and significant DNA damage, thus leading to impaired cell proliferation and genomic instability. These processes may be responsible for disease phenotypes associated with DDX41 mutations.

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Interim FDG-PET analysis to identify patients with aggressive non-Hodgkin lymphoma who benefit from treatment intensification: a post-hoc analysis of the PETAL trial.

A previously developed neural network was employed for iPET analysis to identify the highest pathological FDG uptake (max-SUV . Comprehensive iPET interpretation could identify high-risk patients who benefit from study-specific interventions.

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JAK/BCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL.

This new combination approach efficiently inhibited the growth of human and mouse ETP-ALL cells in vivo by enhancing their differentiation and triggering an apoptotic response. These results set the stage for novel combination therapies to be used in clinical trials to treat ETP-ALL patients.

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METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4.

Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m6A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m6A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors.

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Molecular landscape of immune pressure and escape in aplastic anemia.

These aberrations were not mutually exclusive with PNH and did not correlate with the accumulation of myeloid-driver hits. Our findings shed light on the mechanisms of immune activation and escape in IAA and define alternative modes of clonal hematopoiesis.

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Prognostic value of TARC and quantitative PET parameters in relapsed or refractory Hodgkin lymphoma patients treated with brentuximab vedotin and DHAP.

In conclusion, we established the prognostic impact of sTARC, TARC staining, and quantitative PET parameters for R/R cHL, allowing the use of these parameters in prospective risk-stratified clinical trials. : NCT02280993.

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SF3B1 mutated MDS: Blast count, genetic co-abnormalities and their impact on classification and prognosis.

Recently, MDS with mutated SF3B1 and blast count 5% was not. In conclusion, SF3B1 mut MDS has a favorable prognosis independent of blast count if karyotype and RUNX1 mutations are considered.

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Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia.

The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases.

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Thromb Haemost

External validation of ACUITY/HORIZON bleeding risk score among acute coronary syndrome patients in Thai PCI Registry.

The ACUITY/HORIZON score was successfully validated in contemporary predictive and risk-adjustment models for PCI-related bleeding. The update models had good operating characteristics in patients from a real-world ACS population irrespective of bleeding definitions.

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Impaired platelet function and thrombus formation in PDE5A-deficient mice.

Moreover, PDE5A deficiency reduced phosphatidylserine exposure, calcium mobilization, ROS production and increased intracellular cGMP level along with elevated VASP phosphorylation and reduced phosphorylation of ERK1/2, p38, JNK and AKT. In conclusion, PDE5A modulates platelet activation, function and thrombus formation, indicating that therapeutic targeting it might be beneficial for the treatment of thrombotic diseases.

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Increased Von Willebrand factor platelet-binding capacity is related to poor prognosis in COVID-19 patients.

None.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Am J Hematol

Comprehensive Review on Allogeneic Stem Cell Transplantation for Patients with Myelodysplastic Syndromes.

Recently, a transplant-specific risk score (which includes age, donor type, performance status, cytogenetic category, recipient's cytomegalovirus status, percentage of blasts and platelet count) has shown superiority in transplantation outcome prediction, compared with previous scoring systems. Survival remains low for most patients with TP53 mutations and novel treatment strategies are needed, such as administration of natural killer cells post-transplant, as there is no clear evidence that maintenance therapy after transplantation can improve outcomes.

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Prevention of infections including vaccination strategies in multiple myeloma.

Hence, every effort should be taken to reduce the risk for infections by identifying patients at higher risk for these complications and by implementing prophylactic measures, including chemoprophylaxis and immunization against various relevant pathogens. Here, we review the available evidence and provide recommendations for medical prophylaxis and vaccination in clinical practice.

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Utilization of Real-World Data in Assessing Treatment Effectiveness for Diffuse Large B-Cell Lymphoma.

Results from such studies have been used to supplement regulatory approval of therapies assessed in single-arm trials. While RWD studies have a greater susceptibility to bias compared to randomized controlled trials, well designed and appropriately analyzed studies can provide complementary real-world evidence on treatment effectiveness.

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CA Cancer J Clin

Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians.

Furthermore, as the oncology field seeks to expand indications for immunotherapy, recent data demonstrated that combining durvalumab with standard cytotoxic therapy improved survival in patients with ICC. This review focuses on the current and future strategies for ICC treatment, including a summary of the primary literature for each treatment modality and an algorithm that can be used to drive a personalized and multidisciplinary approach for patients with this challenging malignancy.

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J Hematol Oncol

The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment.

We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.

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Leukemia

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions.

Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.

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Hyperdiploidy: the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children.

Irrespective of this underutilization, however, the detailed genetic characterization of HD leukemias may, especially in planned treatment reduction trials, eventually become important for further treatment stratification, patient management, and the clinical elucidation of outcome data. It should therefore become an integral part of al upcoming treatment studies.

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Miscellaneous

misc publications eg case reports, tools of the trade, images of the month, etc…

Am J Hematol

Abstracts from the 2022 Lymphoma, Leukemia and Myeloma Congress October 18-22, 2022.

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Blood

Anticoagulation-associated AUB after VTE.

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By any other name….

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Clonal hematopoiesis transcending species barriers.

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Connecting the dots: lenalidomide and t-MNs.

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Dangerous B-cell clones.

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Epstein-Barr virus-positive mucocutaneous ulcer of the stomach.

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Forever young: Sphk2 in HSCs, when less is more.

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Impact of Paxlovid on International Normalized Ratio among Patients on Chronic Warfarin Therapy.

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Multiple myeloma presenting with extracellular crystal deposition in the bone marrow.

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Optimized CD19/CD22/CD3 antibody.

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Precision transfusion medicine: a new spin.

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Tackling ALK-positive LBCL.

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The burden of heavy menstrual bleeding.

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The clonal evolution and natural history of MBL.

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WT1 and DNMT3A play essential roles in the growth of certain patient AML cells in mice.

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Blood Adv

An agenda to advance research in MDS: A TOP 10 Priority List from the first international workshop in MDS (iwMDS).

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Clofarabine treatment of KMT2Ar infantile patients with acute lymphoblastic leukemia in St. Jude Total Therapy Study 16.

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DOACs for VTE in patients with brain cancer and brain metastases: choices, choices, choices.

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More on the use of frontline caplacizumab in immune-mediated thrombotic thrombocytopenic purpura.

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Risk of posthospital venous thromboembolism in patients with COVID-19 varies by SARS-CoV-2 period and vaccination status.

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Lancet Haematol

Abortion access and the US medical workforce: a looming crisis for haematology.

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Letters&Replies

Letters to the editors and authors’ replies

J Hematol Oncol

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

org. cn number, ChiCTR1900023309.

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PARP1-MGMT complex underpins pathway crosstalk in O6-methylguanine repair.

Thus, we provide the first mechanistic description of physical interaction between PARP1 and MGMT and their functional cooperation through PARylation for activation of O 6 meG repair. Hence, the PARP1-MGMT protein complex could be targeted for the development of advanced and more effective cancer therapeutics, particularly for cancers sensitive to PARP1 and MGMT inhibition.

Pubmed   Journal   ReadQx   PMC

Leukemia

Finding consistency in classifications of myeloid neoplasms: a perspective on behalf of the International Workshop for Myelodysplastic Syndromes.

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